This invention is directed to the tetradecapeptides ##STR2## in which Y is L-Asn or L-Ala as well as to their pharmaceutically acceptable acid addition salts and to intermediates produced during the synthesis of the tetradecapeptides.
Somatostatin (also known as somatotropin release inhibiting factor) is a tetradecapeptide of the formula ##STR3## This tetradecapeptide was isolated from ovine hypothalamic extracts and was found to be active in inhibiting the secretion of growth hormone (GH), also known as somatotropin. In this regard, see P. Brazeau, W. Vale, R. Burgus, N. Ling, M. Butcher, J. Rivier, and R. Guillemin, Science, 179, 77 (1973).
The biologically active tetradecapeptides of this invention have the formula defined above and include the non-toxic acid addition salts thereof. Their structures differ from that of somatostatin by the presence of a D-valine residue in position 2 in place of a glycine residue, a D-tryptophan residue in position 8 in place of an L-tryptophan residue, and, optionally, an L-alanine residue in position 5 in place of an L-asparagine residue. For convenience sake, the tetradecapeptides of this invention can be referred to as D-Val.sup.2, D-Trp.sup.8 -somatostatin and D-Val.sup.2, L-Ala.sup.5, D-Trp.sup.8 -somatostatin.
Thus, this invention is directed to a compound selected from those of the formula ##STR4## and their pharmaceutically-acceptable non-toxic acid addition salts, and R-L-Ala-D-Val-L-Cys(R.sub.1)-L-Lys(R.sub.2)-Y-L-Phe-L-Phe-D-Trp(R.sub.5)-L -Lys(R.sub.2)-L-Thr(R.sub.3)-L-Phe-L-Thr(R.sub.3)-L-Ser(R.sub.4)-L-Cys(R.su b.1)-X; in which
Y is L-Asn or L-Ala; PA0 R is hydrogen or an .alpha.-amino protecting group; PA0 R.sub.1 is hydrogen or a thio protecting group; PA0 R.sub.2 is hydrogen or an .epsilon.-amino protecting group; PA0 R.sub.3 and R.sub.4 each are hydrogen or a hydroxy protecting group; PA0 R.sub.5 is hydrogen or formyl; and PA0 X is hydroxy or ##STR5## in which the resin is polystyrene; with the proviso that, when X is hydroxy, each of R, R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 is hydrogen, and, when X is ##STR6## each of R, R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are other than hydrogen. PA0 H-l-ala-D-Val-L-Cys-L-Lys-L-Asn-L-Phe-L-Phe-D-Trp-L-Lys-L-Thr-L-Phe-L-Thr-L -Ser-L-Cys-OH; PA0 H-l-ala-D-Val-L-Cys-L-Lys-L-Ala-L-Phe-L-Phe-D-Trp-L-Lys-L-Thr-L-Phe-L-Thr-L -Ser-L-Cys-OH; PA0 N-(boc)-l-ala-D-Val-L-(PMB)Cys-L-(CBzOC)-Lys-L-Asn-L-Phe-L-Phe-D-(For)Trp-L -(CBzOC)-Lys-L-(Bzl)Thr-L-Phe-L-(Bzl)Thr-L- ##STR7## and N-(BOC)-L-Ala-D-Val-L-(PMB)Cys-L-(CBzOC)-Lys-L-Ala-L-Phe-L-Phe-D-(For)Trp- L-(CBzOC)-Lys-L-(Bzl)Thr-L-Phe-L-(Bzl)Thr-L-(Bzl)Ser- ##STR8## PA0 Ala -- Alanine PA0 Asn -- Asparagine PA0 Cys -- Cysteine PA0 Gly -- Glycine PA0 Lys -- Lysine PA0 Phe -- Phenylalanine PA0 Ser -- Serine PA0 Thr -- Threonine PA0 Trp -- Tryptophan PA0 Val -- Valine PA0 Dcc -- n,n'-dicyclohexylcarbodiimide PA0 Dmf -- n,n-dimethylformamide PA0 Boc -- t-Butyloxycarbonyl PA0 Pmb -- p-Methoxybenzyl PA0 CbzOC -- o-Chlorobenzyloxycarbonyl PA0 Cpoc -- cyclopentyloxycarbonyl PA0 Bzl -- Benzyl PA0 For -- Formyl PA0 BpOC -- 2-(p-biphenylyl)isopropyloxycarbonyl